The long-term goal of this proposal is to facilitate the implementation of novel human cell therapies. The success of such treatments much depends on having reliable animal models to perform proof of principle experiments and preclinical studies. Zebrafish have been tested in transplantation experiments such as bone marrow and skin, however, the lack of immune-compatible fish seriously hinders its broad use. We propose to develop a new approach to generate transplantation-compatible zebrafish lines. This new method should be capable of deploying rapidly, at low cost; potentially capitalizing on the extensive and rapidly-expanding library of mutants modeling human disease. Our specific aims are: Aim 1, to develop MHC compatible zebrafish for three strains of fish used by the biomedical community i.e. Tubingen, AB and Casper lines. We will accomplish this aim using somatic cell nuclear transfer. We will produce clones of both sexes from an individual fish that will be subsequently crossed; Aim 2, to demonstrate, using functional studies, the capacity of these animals to tolerate transplanted cells from matched donors without the use of immunosuppression; we will test animals of each generation for their immune compatibility using reciprocal skin transplants. We are addressing a critical barrier in the field by solving the problem of reliably generating immune- compatible zebrafish. In addition, the same strategy can be used for the generation of homozygous zebrafish lines in a considerably shorter period of time. New and already developed mutant zebrafish lines could be re-derived on a homozygous background enhancing their value as model organism.